| Evaluation of endothelial dysfunction with coronary flow reserve measurement in patients with fibromyalgia | |
| DOI: 10.5606/e-cvsi.2023.1500 | |
| Göksel Güz1, Ekrem Bilal Karaayvaz2, Baran Şimşek3 | |
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1Department of Cardiology, Medicana International Hospital, Istanbul, Türkiye 2Department of Cardiology, Istanbul University Faculty of Medicine, Istanbul, Türkiye 3Department of Cardiovascular Surgery, Medicana International Hospital, Istanbul, Türkiye |
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| Keywords: Coronary artery, endothelial dysfunction, fibromyalgia, two-dimensional Doppler echocardiography | |
Objectives: This study aims to investigate the role of increased inflammation and oxidative stress over endothelial functions with
echocardiographic evaluation of coronary flow reserve in patients with fibromyalgia (FM). Patients and methods: Between December 2021 and September 2022, a total of 38 female patients (mean age: 43.4±7.0 years; range, 34 to 51 years) with the diagnosis of FM and 35 healthy controls (15 males, 20 females; mean age: 41.1±6.3 years; range, 34 to 49 years) were included. The endothelial functions were evaluated by measuring coronary flow reserve. Coronary flow reserve of the left anterior descending coronary artery was measured from distal and middle portions with pulse wave Doppler at both baseline and hyperemic peak diastolic flow rate by transthoracic echocardiography. Results: There were no significant differences in clinical, demographical and laboratory findings between the FM and control group, except for conventional C-reactive protein (CRP) levels. The mean hyperemic peak diastolic flow rate and coronary flow reserve values were significantly lower in FM patients (p<0.001). Conclusion: Chronic stress and pain augment the sympathetic activity, resulting in endothelial dysfunction and increasing the cardiovascular risk. Endothelial dysfunction should be evaluated by measuring coronary flow reserve in FM patients. |
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Fibromyalgia (FM) is defined as a chronic
syndrome characterized with widespread
musculoskeletal pain, fatigue, sleep disturbances,
cognitive symptoms, anxiety, and depression.[1]
Genetic, neurological, and immunological disorders
are known to be the etiological causes of FM.[2]
The prevalence of FM is reported to be 5.4% and
increases with age, reaching a peak around the
seventh decade of life and, at every age, it is more
common in women than in men.[3] Risk factors
include genetic disorders, female sex, and additional
painful conditions. According to the 2010 American
College of Rheumatology (ACR) criteria, FM has an
approximately 2:1 female-to-male predominance and
is reported to be 20 to 30% in patients with systemic
lupus erythematosus and rheumatoid arthritis.[4]
Symptoms and signs of FM are chronic (>3 months)
widespread or multisite pain (≥6 of 9 body regions),
fatigue, cognitive problems, sleep disturbances, other
somatic symptoms (paresthesia, abdominal pain,
headaches, dizziness) and significant soft tissue tenderness on physical examination. The differential
diagnosis includes neurological, rheumatological,
endocrine and infectious disorders. Although the pathophysiology of FM has not yet been fully elucidated, endothelial dysfunction and inflammation have been suggested to occur in patients with FM.[5] There is a cerebral blood flow variability in FM patients with a positive correspondence between the emotional and cerebral functional variables which suggests a connection between both cerebral and vascular dysfunction.[6] The increase and overstimulation in sympathetic activity should be the main reason for the endothelial damage which can enhance the vascular response.[7] The enhanced vascular response may lead to endothelial dysfunction and damage which probably causes endothelium-mediated atherogenesis.[8] With regard to endothelial nitric oxide (NO) and/or endothelial-derived endothelin 1 (ET-1) releasing defects and decreases in serum NO and/or ET-1 levels, endothelium-related vasodilatation significantly reduces.[9] It has been reported that baroreflex sensitivity reduces in FM patients which accompanies the risk of endothelial dysfunction and enhanced arterial stiffness due to autonomic dysfunction.[10] Endothelial dysfunction is one of the primary causes of atherosclerosis and, thus, inadequate vasodilatory response and endothelial dysfunction includes increased proinf lammatory and prothrombotic states.[11] Endothelial functions can be evaluated with the coronary flow reserve (CFR), which is also known as myocardial flow reserve. It can be measured with both transthoracic and transesophageal echocardiography or invasively with a Doppler-tipped coronary guidewire to determine coronary velocity. A CFR value is defined as the ratio between the hyperemic peak diastolic flow rate (HPDFR) and baseline peak diastolic flow rate (BPDFR) assessed from middle or distal left anterior descending coronary artery (LAD). The normal value for CFR is 2 to 3, whereas ≤2.0 is considered abnormal.[12] Reduced CFR revealing coronary microcircular dysfunction has been suggested to be the early sign of atherosclerosis.[12] Early stages of the atherosclerotic coronary artery disease is often associated with abnormal resistance of the coronary arteries before obvious stenosis.[13] Diffuse atherosclerotic disease of the epicardial coronary arteries frequently causes impaired CFR which may contribute to myocardial ischemia and perfusion deficiency. |
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This single-center, prospective study was
conducted at Medicana International Istanbul
Hospital Department of Cardiology between
December 2021 and September 2022. The
study group included 38 female patients
(mean age: 43.4±7.0 years; range, 34 to 51 years)
who were admitted to either Physical Medicine and Rehabilitation or Rheumatology outpatient clinics
of our hospital and diagnosed with FM according
to the 2016 revised ACR criteria. The control group
was consisted of 35 healthy, asymptomatic, and
very low-risk individuals (15 males, 20 females;
mean age: 41.1±6.3 years; range, 34 to 49 years) in
terms of endothelial dysfunction who were admitted
for a regular check-up with no cardiovascular or
other systemic diseases. The control group was
mainly consisted of those without hyperlipidemia,
dyslipidemia and who did not smoke. Exclusion
criteria included coronary artery disease, significant
valvular heart disease, diabetes mellitus, hypertension,
hyperlipidemia, dyslipidemia, psychiatric disease,
and thyroid dysfunction. Demographic, clinical, and
laboratory data of both groups were recorded. Routine transthoracic echocardiographic evaluations were performed with VIVID 7 (General Electric, Horten, Norway) by using 3 MHz probe in the left lateral supine position. M-mode echocardiography and 2D measurements were performed according to the American Society of Echocardiography (ASE) guidelines.[14] All CFR measurements were performed with apical two-chamber long-axis imaging of left ventricle. The middle and distal LAD flow was visualized by color Doppler with an optimal velocity of 12 to 15 cm/sec. Coronary flow of the middle or distal LAD was examined over the epicardial part of the anterior left ventricular wall by color Doppler flow mapping (Figure 1a). The BPDFR was measured initially. All patients had Doppler recordings with a dipyridamole infusion at a rate of 0.56 mg/kg over 4 min. Continuous heart rate and electrocardiographic monitoring was performed simultaneously, as well as blood pressure recordings at baseline, during dipyridamole infusion, and recovery. If the heart rate was increased less than 10% compared to baseline, additional 0.28 mg/kg of dipyridamole infusion over 2 min was administered intravenously. After recovery, the HPDFR was measured. The CFR was calculated by the ratio of the HPDFR-to-BPDFR. A CFR value between 2 and 3 considered normal, whereas <2 values were considered abnormal. The HPDFR measurements using M-mode echocardiography and two-dimensional (2D) Doppler echocardiography of a patient with FM and a healthy control are presented in Figure 1b, c.
Statistical analysis |
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Demographic, clinical, and laboratory data of
the patients and healthy controls are summarized
in Table 1. There were no significant differences
in demographic, clinical, and laboratory findings
between the FM and control group, except for the mean conventional CRP levels which were 2.29±1.39
(range, 0.6 to 3.8) mg/mL in the patient group and
1.49±1.04 (range, 0.5 to 2.9) mg/mL in the control
group, respectively (p=0.019). Table 1 Demographic, clinical, and laboratory data of study participants The mean global left ventricular ejection fraction (LVEF), end-diastolic (ED) septum and posterior wall (PW) thicknesses, and BPDFR measurements were all within normal ranges for both the patient and control groups. However, the mean HPDFR and CFR values were significantly lower in FM patients (p<0.001). The transthoracic echocardiographic parameters of all participants are given in Table 2. Table 2 Transthoracic echocardiographic parameters of the FM and control group patients Diagnostic accuracy of CRP, HPDFR, and CFR values with the ROC diagrams and the ANOVA analysis are depicted in detail in Figure 2. Accordingly, conventional CRP levels, HPDFR and CFR values of the fibromyalgia patients were quantifying a diagnostic accuracy within the endothelial dysfunction. |
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The main objective of our study was to investigate
the role of increased inflammation and oxidative
stress over endothelial functions with transthoracic
echocardiographic evaluation of the CFR and HPDFR
in patients with FM. The primary endpoint of the study
was to evaluate endothelial dysfunction which should
be determined by CFR and HPDFR measurements
to prove FM as a cardiovascular risk factor. The
CFR is a combined measurement of the vasodilator
capacity of coronary microcirculation, which is an
independent predictor of long-term prognosis
of atherosclerosis.[15] We evaluated endothelial
dysfunction which was revealed by decreased levels
of CFR and HPDFR in patients with FM. Our study
results showed that HPDFR and CFR values were
significantly reduced in FM patients. In addition,
conventional CRP values were also higher in these
patients. Similarly, Bote et al.[16] confirmed that FM
patients had an inflammatory state accompanied by
an altered stress response. This is mainly manifested
by high circulating levels of interleukin (IL)-8 and
CRP (in 100% of the FM group). There is also
an increased release of inflammatory cytokines
(IL-1b, tumor necrosis factor-alpha, IL-6, IL-10,
IL-18 and monocyte chemoattractant protein-1) by
monocytes, and enhanced activation of the functional
capacity of neutrophils (chemotactic, phagocytic and
fungicidal activities).[16] The etiopathogenesis of FM is
multifactorial. Apart from neurohormonal and genetic
factors, increased inflammatory activity and oxidative
stress are known to play a role in the development of
FM.[16,17] Thus, data on CRP are also controversial.
A large-scale study showed a positive association
between CRP and FM.[18] However, this association
was attenuated after adding body mass index and comorbidities in the model. The fact that these
conditions, which are included in the pathophysiology
of endothelial dysfunction and atherosclerosis,
suggests that the endothelial functions of patients
with FM may also be impaired and, thus, FM and
endothelial dysfunction may accompany. Endothelial
cells and endothelium-derived cytokines are other
modulators of inflammation. A study by Mertoglu et
al.[5] revealed that the level of endocan, a proteoglycan
produced by endothelial cells, was significantly higher
in patients with FM, compared to healthy controls.
Increased levels of cytokines induced by inflammatory
reaction and catecholamine-induced endothelial
damage including microvascular spasm may be related
with the pathophysiological mechanisms of decreased
CFR in FM patients.[8] Vascular endothelial cells
modulate the vascular tone either by secreting relaxing
or constructing mediators. The ET1 is one of the
potent vasoconstrictor peptides which is oversecreted
by the endothelium and the vascular smooth cells
as a result of inflammatory conditions. These levels
increase in patients with FM.[8] Coronary microvascular spasm plays a major role in affecting myocardial ischemia in patients without obstructive coronary artery disease and also associated with female predominance.[19] Similarly, Suwaidi et al.[20] reported that coronary endothelial dysfunction without obstructive coronary lesions was significantly associated with advanced cardiovascular disease. Likewise, endothelial and microvascular dysfunction, abnormal neurohormonal activity, and small vessel disorders may lead to coronary slow flow which ranges from 1 to 6% among patients with suspected coronary artery disease.[21] The coronary circulation may be sensitized to the circulating vasoconstrictor catecholamines by microvascular endothelial dysfunction in terms of inflammatory processes. Nevertheless, chronic pain may impair coronary circulation as a result of immoderate triggering of sympathetic nervous system (SNS) in FM patients.[22] Increased sympathetic activity can change cardiovascular responses and cause endothelial dysfunction. Nitric oxide, which is produced by catalyzing L-arginine, has a critical function in vasodilatation. Activated SNS decreases endothelial-derived vasodilatation caused by a loss of NO bioavailability in the vessel wall, although this process limits the relaxation ability of the artery and impairs the smooth cell functions.[23] The link between the immune and nervous systems is implicated in the pathophysiology of FM-related vascular disorders. Flow-mediated vasodilation (FMD) test is the most accepted non-invasive test which reflects arterial endothelial-mediated vasomotor function.[24] Due to possible side effects of the administered drugs or invasive patterns of procedures to evaluate the endothelial functions, endothelial function measurement through FMD shows high accuracy.[25] Cardiovascular diseases are considered major causes of morbidity and mortality.[26] Patients with FM can be also evaluated regarding the cardiovascular risk factors. Reducing the pain and diminishing the severity of disease can be crucial to prevent cardiovascular risk factors in patients with FM. Our findings suggest that CFR is a possible predictor of long-term prognosis of atherosclerosis in FM patients which would call attention to the long-term impacts of living with FM. Further studies are, therefore, required to confirm FM as a cardiovascular risk factor. The fact that the entire population in the patient group was female is the main limitation to this study. During the study period, no male patients were admitted to either Physical Medicine and Rehabilitation or Rheumatology outpatient clinics of our center with the diagnosis of FM. Additionally, the menstrual cycle of the patients were not considered and different hormonal phases may have affected cardiovascular variables. Finally, the findings of our study are only preliminary data and further large-scale, prospective studies are needed for future considerations about coronary flow dynamics in FM patients. In conclusion, chronic stress and pain augment the sympathetic activity, resulting in endothelial dysfunction and increasing the cardiovascular risk. Endothelial dysfunction should be evaluated by measuring coronary flow reserve in FM patients. Ethics Committee Approval: This was a prospective and single-center study which was approved by the Medicana International Istanbul Hospital Ethics Committee (date: 03.11.2021, no: 022) and was conducted by the principles of the Helsinki Declaration. Ethical consent had also been obtained for intravenous drug administration during the CFR measurements. Patient Consent for Publication: A written informed consent was obtained from each patient. Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. Author Contributions: Idea/concept, data collection and/or processing, design: G.G.; Design, analysis and/or interpretation: E.B.K.; Literature review, writing the article, critical review: B.Ş. Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. Funding: The authors received no financial support for the research and/or authorship of this article. |
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